1. Field of the Invention
The present invention relates to an improved spherical-like encapsulated aminoglycoside, specifically gentamicin, formed by means of a two-phase system, and to a method for preparing such a spherical-like encapsulated product. The present invention also provides a method for introducing gentamicin into a patient orally without significant degradation of the gentamicin stomachically.
2. Description of the Prior Art
The aminoglycosides are composed of aminosugars connected to a central hexose by glycosidic linkage. Most aminoglycosides are prepared by natural fermentation from various species of Streptomyces, or in the case of gentamicin, from Micromonspora. In general, aminoglycosides have similar antibacterial spectra and pharmacokinetic properties. The drugs contain one or two aminosugars glycosidally linked to an aminocyclitol nucleus and are more accurately termed aminoglycosidic aminocyclitols. The aminocyclitol nucleus of gentamicin and the closer related drugs such as kanamycin, neomycin etc. is true dioxystreptomycin.
Although the invention is directed to the aminoglycosides generally, the member of this group that is of most interest is gentamicin. Gentamicin is an aminoglycoside antibacteric indicated in the treatment of several gram-negative infections, primarily pseudomonas infections, including complicated urinary tract infections, bacteremia and intra-abdominal infections. The drug has proved useful in serious infections in burned patients, respiratory tract infections, endophtalmitis, osteomyelitis, Serratia infections, antibiotic-resistant meningitis and severe diarrhea in infants.
Under aerobic conditions, the aminoglycosides are bactericidal, but their exact mechanism of action is unknown. They must be actively transported into susceptible bacteria. Based on the studies of Pratt, done primarily with streptomycin in 1977, the aminglycosides bind to the bacterial 30S ribosomal subunit to produce a nonfunctional 70S initiation complex that, in turn, results in the inhibition of bacterial cell protein synthesis and misreading of the genetic code. All of the aminoglycosides bind to the 30S subunit, and most of them appear to have additional interactions with this subunit when compared to streptomycin.
It is not known why the aminoglycosides are bactericidal, while other antibiotics such as the tetracyclines, for example, that impair protein synthesis are usually only bacteriostatic. Bacterial cell death does not appear to correlate with the production of faulty proteins due to the misreading of the genetic code. Pratt in his 1977 work suggested the lethal effect of the animoglycosides may result from their high affinity for the 30S subunit that leads to irreversible binding, but other mechanisms, such as effects on bacterial membranes, also may be involved.
U.S. Pat. No. 3,136,704 to Charney describes a method for production of gentamicin by a gentamicin producing strain of micromonospora in aqueous nutrient medium under aerobic consitions.
U.S. Pat. No. 3,091,572 to Luedemann et al describes a method of preparing gentamicin by cultivation under controlled conditions of a species of the genus micromonospora of the order actinomycetales.
Heretofore, gentamicin has not been effectively administered orally and correspondingly has been given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous injection. The intramuscular route of administration has been avoided because of the frequent occurrence of hematoma at the injection site. In addition, intramuscular injection of gentamicin frequently causes local irritation, and pain.
Saffran et al. disclose in Science Vol. 223, pages 1081-1084 (1986), that oral administration of certain peptide drugs is well known to be precluded by their digestion in the stomach and small intestine. As a new approach to oral delivery, they propose to coat the peptide hormones vasopressin and insulin with polymers cross-linked with azoarmatic groups to form an impervious film, which protects these drugs, when orally administered, from digestion in the stomach and small intestine. When these polymer-coated drugs reach the large intestine, the indigenous microflora reduce the azo bonds, break the cross-links, and degrade the polymer film, thereby causing release of either the coated peptide hormones, vasopressin or insulin, into the lumen of the colon for local action, or for absorption.
It is readily apparent that the prior art has provided a number of approaches for preparing compounds which introduce drugs into a patient. However, none of these prior art attempts has been successfully applied to oral administration of gentamicin.
These and other defects and disadvantages, of the prior art practice of administering gentamicin into a patient, are now overcome by practice of the present invention.